Opposing effects of prostaglandin E receptors EP3 and EP4 on mouse and human β-cell survival and proliferation.

•EP3 inhibits mouse and human β-cell proliferation and increases β-cell death.•Inhibition of EP3 acts in part via PLC-γ1 to increase mouse β-cell proliferation.•EP4 enhances human but not mouse β-cell proliferation in the presence of EP3 inhibition and promotes β-cell survival in mouse and human islets.•EP4 acts through a PKA-dependent mechanism to protect against mouse β-cell death.•Pro-survival effects of FoxM1 activation are inhibited by EP3 and dependent on EP4.